: Auditory Mechanics and Cochlear Amplification Sound input to the inner ear (cochlea) causes a frequency-segregated wave-pattern of sensory tissue motion that conveys sound information to the auditory neurons, leading to hearing. A currently untreatable aspect of hearing impairment is the deterioration of the cochlea's ability to sharply segregate sound by frequency. The cochlea's healthy frequency tuning is largely provided by the cochlear amplifier, an outer-hair-cell-driven, place-frequency-localized electromechanical engine that is both powerful and fragile. This project's aims 1-3 explore the cell/structure basis of cochlear amplification. The studies use intracochlear micro-sensors that have been developed, enhanced and used in our laboratory over the past 20 years, along with a cutting-edge imaging technology, spectral- domain optical-coherence-tomography. With these tools, localized measurements of mechanical and electrical responses at and within the cochlea's sensory tissue will be made before and after treatment by auditory-active substances. These substances are cochlear-perfused Tributyltin, which increases intracellular Cl- and thus alters prestin-based OHC activity, and systemically-injected Furosemide, a loop diuretic that reduces endocochlear potential. The analysis of simultaneously measured responses (endocochlear potential, pressure at and motion of the sensory tissue, outer-hair-cell- derived extracellular voltage) will inform our understanding of the workings of the cochlear amplifier, and the ways in which it fails. These intracochlear experiments form the primary overarching theme of the project. The second theme of the project explores the transmission of sound to the cochlea by the middle ear, a mechanical process that remains unexplained. In particular, while the mechanical response of the middle ear's tympanic membrane appears to be a poor representation of the incoming sound, the middle ear is nevertheless able to transmit sound to the inner ear with high fidelity. This ability has been the subject of physics-based theories and we will test those theories by investigating the transmission of an impulse sound stimulus in motion measurements from the tympanic membrane's outer edge to the ossicular malleus.